1. Field of the Invention
The present invention provides novel tetra substituted olefin compounds which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, therefore, are useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The present invention also provides novel processes for the preparation of the tetra substituted olefin compounds and to certain intermediates in their preparation.
2. Disclosure Statement
The natural fermentation products Compactin (R=H) disclosed by A. Endo, et al. in Journal of Antibiotics, 29, 1346-1348 (1976) and Mevinolin (R=CH.sub.3) disclosed by A. W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A. 77, 3957 (1980) are very active antihypercholesterolemic agents which limit cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase, the rate-limiting enzyme and natural point of cholesterogenesis regulation in mammals, including man. Compactin (R=H) and Mevinolin (R=CH.sub.3 ; also known as lovastatin) have the structures shown below: ##STR3##
A number of structurally related synthetic compounds useful in the treatment of hypercholesterolemia have also been disclosed in patents and other publications. The synthetic art most closely related is as follows:
U.S. Pat. No. 4,198,425, issued Apr. 15, 1980 to S. Mistui, et al. describes novel mevalonolactone derivatives useful for the treatment of hyperlipidemia and having the general formula ##STR4## wherein A represents a direct linkage, methylene, ethylene, trimethylene or vinylene group and R.sup.3, R.sup.4 and R.sup.5 represent various substituents.
International patent application WO 84/02131 published June 7, 1984 describes analogs of mevalonolactone having the structure ##STR5## wherein: one of R and R.sup.0 is ##STR6## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl--(CH.sub.2).sub.n --;
X is --(CH.sub.2).sub.n -- or --CH=CH--; PA1 n is 0, 1, 2 or 3; PA1 Z is ##STR7## and R.sup.4, R.sup.5, R.sup.5a and R.sup.6 represent various substituents. PA1 m is 0, 1, 2 or 3 and PA1 Z is ##STR16## PA1 R is C.sub.1-7 alkyl, C.sub.3-6 cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl; PA1 A is ##STR21## R.sup.5 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt. PA1 and R.sup.4 each are independently hydrogen, fluoro, chloro, methyl or methoxy; PA1 R C.sub.1-7 alkyl, C.sub.3-6 cycloalkyl, fluoromethyl, difluoromethyl or trifluoromethyl; PA1 A is ##STR34## R.sup.5 is hydrogen, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt.
International patent application WO 84/02903 published Aug. 2, 1984 describes mevalonolactone analogs having the structures ##STR8## wherein X is --(CH.sub.2).sub.n --, ##STR9## n=0, 1, 2, or 3 and both q's are 0 or one is 0 and the other is 1 and ##STR10##
In J. Med. Chem., 28, 347-358 (1985), G. E. Stokker, et al. report the preparation and testing of a series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives.
In J. Med. Chem., 29, 159-169 (1986), W. F. Hoffman, et al. describe the preparation and testing of a series of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactone derivatives. One of the preferred compounds in the reported series has the structure ##STR11##
In J. Med. Chem., 29. 170-181 (1986), G. E. Stokker, et al. report the synthesis of a series of 7-[3,5-disubstituted (1,1'-biphenyl)-2-yl]-3,5-dihydroxy6-heptenoic acids and their lactones. Two of the preferred compounds reported in this article have the structures ##STR12##
U.S. Pat. No. 4,613,610, issued Sept. 23, 1986 to J. R. Wareing describes pyrazole analogs of mevalonolactone and its derivatives useful for the treatment of hyperlipoproteinemia and atherosclerosis and having the general formula ##STR13## wherein X is --(CH.sub.2).sub.n --, --CH=CH--, --CH=CH--CH.sub.2 -- or --CH.sub.2 --CH=CH--; n is 0, 1, 2 or 3, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Z represent various substituents.
International patent application WO 86/07054 published Dec. 4, 1986 describes imidazole analogues of mevalonolactone having the general formula ##STR14## wherein R.sup.1, R.sup.2 and R.sup.3 are C.sub.1-6 alkyl not containing an asymmetric carbon atom, C.sub.3-7 cycloalkyl, adamantyl-1 and R.sup.3 may also be styryl or R.sup.1, R.sup.2 and R.sup.3 are ##STR15## respectively, wherein R.sup.4 to R.sup.13 are various substituents; X is --(CH.sub.2).sub.m --, --CH=CH--, --CH=CH--CH.sub.2 or --CH.sub.2 --CH=CH.sub.2 --
wherein
U.S. Pat. No. 4,681,893 issued July 21, 1987 to B. D. Roth describes certain pyrrol-1-yl compounds which are useful as hypochloesterolemic and hypolipidemic agents having the general formula ##STR17## wherein X is --CH.sub.3 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, or CH.sub.2 CH(CH.sub.3)--; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 represents various substituents.
U.S. Pat. No. 4,735,958 issued Apr. 5, 1988 to B. D. Roth et al describes certain pyrrol-1-yl compounds which are useful as hypocholesterolemic and hypolipidemic agent having the general formula ##STR18## wherein R.sup.1, R.sup.2, R.sup.3 and Het represent various substituents.